A Defective Response to Hedgehog Signaling in Disorders of Cholesterol Biosynthesis

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A Defective Response to Hedgehog Signaling in Disorders of Cholesterol Biosynthesis letter A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis Michael K. Cooper1,2,5, Christopher A. Wassif3, Patrycja A. Krakowiak3, Jussi Taipale1, Ruoyu Gong1, Richard I. Kelley4, Forbes D. Porter3 & Philip A. Beachy1 Published online 24 March 2003; doi:10.1038/ng1134 Smith–Lemli–Opitz syndrome (SLOS), desmosterolosis and lath- additional role for cholesterol in Hh signal response was sug- osterolosis are human syndromes caused by defects in the final gested by the observation that cyclopamine and jervine, terato- stages of cholesterol biosynthesis. Many of the developmental genic plant alkaloids that block Hh signaling, also inhibit malformations in these syndromes occur in tissues and struc- cholesterol transport and synthesis2,3. But cyclopamine has since tures whose embryonic patterning depends on signaling by the been shown to specifically inhibit Hh signaling by binding to a Hedgehog (Hh) family of secreted proteins. Here we report that pathway component4, and the doses of these alkaloids required response to the Hh signal is compromised in mutant cells from to inhibit Hh signaling are lower than those required to block mouse models of SLOS and lathosterolosis and in normal cells cholesterol transport (ref. 5 and M.K.C., unpublished data). pharmacologically depleted of sterols. We show that decreas- To determine how cholesterol may affect Hh signaling in embry- ing levels of cellular sterols correlate with diminishing respon- onic development, we exposed chick embryos to cyclodextrin, a http://www.nature.com/naturegenetics siveness to the Hh signal. This diminished response occurs at cyclic oligosaccharide that forms non-covalent complexes with sterol levels sufficient for normal autoprocessing of Hh protein, sterols6 and can be used to extract and deplete cholesterol from liv- which requires cholesterol as cofactor and covalent adduct. We ing cells7. Cyclodextrin treatment caused variable loss of the fron- further find that sterol depletion affects the activity of tonasal process and other midline structures (Fig. 2a), and the Smoothened (Smo), an essential component of the Hh signal spectrum of facial defects was similar to that resulting from expo- transduction apparatus. sure to the Hh-pathway antagonist jervine3. The most severely The role of cholesterol in Hh protein biogenesis suggested that affected embryos developed a proboscis-like structure that pheno- impaired Hh autoprocessing might underlie some of the devel- copies the nasal rudiments of mouse embryos that are homozygous opmental abnormalities in SLOS (Fig. 1 and Table 1; ref. 1). An with respect to mutations in the gene Sonic hedgehog (Shh; ref. 8). Fig. 1 Cholesterol biosynthesis and a b Hh pathway. a, Autosomal recessive HMG CoA disorders with multiple developmen- - SLOS © Group 2003 Nature Publishing HMG-CoA reductase tal anomalies are associated with lathosterolosis three different enzymatic defects HhNp (represented by solid colored lines) 3 8 desmosterolosis 4 in the final steps of the cholesterol HO 7 lanosterol 6 biosynthesis pathway. SLOS results Ptc Smo from defects in DHCR7 (red line), palmitate lathosterolosis from defects in SC5D (green line) and desmosterolosis from 24 cholest-7,24- lathosterol defects in 3-β-hydroxysterol-∆ - HO HO en-3β-ol cholesterol reductase (yellow line). Steps in sterol synthesis not shown are indicated by Gli proteins multiple arrows. b, After cleavage of Hh precursor protein the signal sequence (black box), the Hh precursor undergoes an internal 7-dehydro- 7-dehydro- HO HO cleavage reaction mediated by desmosterol cholesterol sequences in the C-terminal autopro- Ptch cessing domain (white box). Choles- terol participates in the reaction and nucleus nucleus remains esterified to the newly desmosterol cholesterol Hh-generating cell Hh-responding cell formed C terminus of the signaling HO HO domain (shaded box). Fully processed, secreted Hh proteins (designated HhNp, p for processed) also receive an N-terminal palmitoyl group in a reaction requiring the acyltransferase Skinny hedgehog30. The response to Hh is regulated by two transmembrane proteins, Ptch (in red) and Smo (in green). Ptch suppresses the activity of Smo, and Hh binding to Ptch inhibits this function (–), leading to Smo activation of a transcriptional response through the Gli family of transcription factors. Ptch is a transcriptional target of Hh signaling and thus forms a neg- ative feedback loop that ensures adequate regulation of Smo in the absence of Hh. Multiple arrows indicate the participation of a complex of Hh signaling com- ponents not shown. Departments of 1Molecular Biology and Genetics and 2Neurology, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. 3Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1830, USA. 4Kennedy Krieger Institute, Baltimore, Maryland 21205, USA. 5Present address: Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA. Correspondence should be addressed to P.A.B. (e-mail: [email protected]). 508 nature genetics • volume 33 • april 2003 letter Table 1 • Developmental malformations in tissues patterned by Hh signaling Hh family Source of Target Normal role of Consequence of member Hh signal tissue Hh signaling disrupted Hh signaling PHS25 SLOS25 Lath26 Des27 Prechordal plate Ventral Formation of Holoprosencephaly + + – + mesendoderm neuroectoderm midline forebrain and ectoderm and mesenchyme and facial of facial processes of facial processes structures Sonic Posterior limb bud Limb bud Patterning of the Post-axial + + + hedgehog mesenchyme mesenchyme autopod and polydactyly and + + + and ectoderm zeugopod syndactyly Lung bud Lung bud Branching Unilobular + + epithelium mesoderm morphogenesis lungs of lung Prehypertrophic Chondrocytes Regulation of Rhizomelia + + chondrocytes and osteoblasts endochondral Indian bone growth hedgehog Colonic Neural crest Development of Aganglionic + + epithelium cells (?) the enteric megacolon nervous system (Hirschsprung disease) Desert Sertoli cells Leydig cells Development of the Cryptorchidism/ +/+ +/+ +/+ +/– hedgehog male gonad ambiguous genitalia or hypospadias Overlap of developmental anomalies in tissues patterned by members of the mammalian family of Hh signaling proteins28 among individuals with Pallister–Hall syndrome (PHS), SLOS, lathosterolosis (Lath) and desmosterolosis (Des). PHS is an autosomal dominant disorder associated with mutations in GLI3 that reduce transcriptional activation of Hh pathway targets29. http://www.nature.com/naturegenetics We further investigated Shh signaling in embryonic tissues by HNF3β (hepatocyte nuclear factor 3β or forkhead box A2; ref. 3), exposing chick neural-plate explants to recombinant Shh protein an indicator of floor plate fate. This high-threshold response was (ShhN, 30 nM) in the presence of cyclodextrin (Fig. 2b). The blocked in the presence of 400 µM cyclodextrin and replaced by response to this level of ShhN protein was uniform production of nearly uniform expression of ISL1, an intermediate-threshold a definitive embryonic streak stage day 5 Fig. 2 Cyclodextrin treatment inhibited Shh signaling. a, CD 375 µM Cyclodextrin treatment of chick embryos in ovo caused holoprosencephaly. Scanning electron micrographs of facial experimental timeline features at embryonic day 5 of a control (control) chick embryo and of embryos exposed to 375 µM cyclodextrin lnp * (CD). Cyclodextrin treatment at the early-primitive-streak * * stage led to variable loss of midline tissues, primarily the fnp * frontonasal process (fnp), and approximation or fusion of opt mx paired lateral structures, such as the lateral nasal processes © Group 2003 Nature Publishing mn (lnp), optic vesicles (opt) and the maxillary (mx) and control CD CD CD mandibular (mn) processes. The slanting nostrils of less severely affected chick embryos treated with cyclodextrin resembled the anteverted nares characteristic of SLOS. Com- b ShhN intermediate neural plate explant assay plete loss of the frontonasal process and subsequent fusion CD of the lateral nasal processes (marked by the asterisk at the 48 h experimental timeline top border of the lateral nasal process) led to the formation of a proboscis with a single nasal pit, positioned above fused optic vesicles. b, Cyclodextrin treatment inhibited the cellu- lar response to Shh protein. Confocal microscope images of HNF3β stage 9–10 chick embryo ectoderm dissected from a region of the neural plate intermediate to the notochord and roof plate and just rostral to Hensen’s node. Explants were cul- tured for 48 h in collagen and stained for HNF3β (red) or ISL1 (green). Neural progenitor cells explanted from this position and at this developmental stage did not express markers of either floor-plate (HNF3β) or motor-neuron (ISL1) cell fates. Addition of 30 nM ShhN at the onset of cul- ISL1 ture induced a high-threshold response indicated by the expression of HNF3β. In the presence of 400 µM cyclodex- trin, however, HNF3β induction was completely blocked. ISL1 expression is indicative of an intermediate-threshold ShhN (nM) 0 30 30 30 response and was not present with 30 nM ShhN. But, in the CD (µM) 0 0 200 400 presence of 200 and 400 µM cyclodextrin, partial inhibition of the high-threshold signaling dose of 30 nM ShhN pro- dorsal neural plate and epidermal ectoderm explant duced the intermediate-threshold response
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